Abstract PS2-02-07: Impact of BRCA homozygous copy loss on clinical outcomes of patients (pts) with metastatic breast cancer (MBC) treated with PARP inhibitors (PARPi)

Abstract Background: PARPi are used to treat MBC, particularly in pts with genomic alterations (GA) in BRCA1/2 by targeting homologous recombination deficiency (HRD). This study explored clinical and genomic factors associated with PARPi sensitivity in a real-world MBC cohort. Methods: This retrospective study included 290 pts with MBC who had genomic testing via FoundationOne/FoundationOne CDx tissue comprehensive genomic profiling (CGP) and prior to treatment with a PARPi. Clinical data were sourced from the US-wide de-identified Flatiron Health-Foundation Medicine clinic genomic database, including ∼800 sites across ∼280 US cancer clinics (Jan 2011-Dec 2024). HRD alterations (alts) were defined as mutations, homozygous copy loss, or structural rearrangements in any of the following genes: BRCA1/2, ATM, ATR, ATRX, BAP1, BARD1, BRIP1, CHEK1/2, CDK12, FANCA, FANCL, MRE11, RAD51B/C/D, RAD54L or PALB2. HRD signature (HRDsig) status, which is offered as a laboratory professional service, was calculated using genome-wide copy number features, with scores from 0 to 1 and a predefined cutoff of 0.7 to call HRDsig (+). BRCA1/2 germline status was inferred using a validated somatic-germline-zygosity algorithm. Time to next treatment or death (TTNT) on PARPi was analyzed using Cox models adjusted for clinical variables. Results: Among 290 pts, most were female (96.6%, n=280), with a median age of 57 years at PARPi initiation. Of these, 186 (64.1%) had hormone receptor-positive (HR+) disease and 104 (35.9%) had HR- disease. In total, 21 had HER2+ tumors (12 HR+, 9 HR-). PARPi was given +/- endocrine therapy in 236 pts (81.4%) and in combination with other therapies in 54 (18.6%). PARPi was given in 1L (14.1%), 2L (26.9%), 3L (19.3%), and ≥4L (39.7%). Tumors from 199 patients (59.2%) were HRDsig (+): 120 (60.3%) HR+ and 79 (39.7%) HR−. Overall, 237 pts (81.7%) harbored ≥1GA (mutation, homozygous copy loss, or rearrangement) in BRCA1 (n=90), BRCA2 (n=130), or PALB2 (n=19). Nineteen pts had BRCAloss (8 in BRCA1 and 11 in BRCA2). In pre-PARPi CGP samples, HR+ tumors most frequently harbored BRCA2 (52.7%), TP53 (32.8%), BRCA1 (21.0%), while HR- tumors showed higher rates of TP53 (85.6%), BRCA1 (49.0%), BRCA2 (30.8%), and PALB2 (4.8%). Among pts with HR+ disease, those with a BRCAloss vs other BRCA GA detected prior to PARPi exposure had more favorable TTNT (median 15.2 vs. 8.5 months HR:0.40; p=0.012). No differences in TTNT were observed by BRCA1/2 mutation origin (germline (g) vs somatic (s)), type (truncating vs missense), or location (Table 1). Conclusions: Response to PARPi varied across different GA. Among pts with HR+ MBC, those with BRCAloss appeared to derive the greatest benefit. These findings highlight the potential utility of CGP in guiding PARPi treatment decisions. Citation Format: A. Rodríguez-Hernández, J. Quintanilla, R. Graf, A. Schrock, A. Gasco, B. Bychkovsky, R. Kitadai, S. Morganti, D. Abravanel, S. Tolaney, J. Garber, R. Jeselsohn, N. Lin, F. Lynce. Impact of BRCA homozygous copy loss on clinical outcomes of patients (pts) with metastatic breast cancer (MBC) treated with PARP inhibitors (PARPi) abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-02-07.